August 8 - 11, 2005, DDT 2005, Boston, MA, USA

Reducing the Synthetic Burdens of Lead Structure Optimization: A Novel Software-Aided Approach

Karim Kassam, Ryan Sasaki, Michel Hachey, Fedor Gorohov, and Eduard Kolovanov

Abstract

Biological activity of a drug is contingent on its ability to cross one or more barriers in order to get into the intended sites of action. The ability to deliver the drug to the target sites is greatly influenced by the compound's physiochemical properties (logP, pK_a, aqueous solubility, etc.). After library screening, it can be beneficial to optimize the properties of selected lead compounds by making small structural changes. One of the major challenges of this work is to employ modifications that optimize the desired properties without introducing negative effects on the lead's activity or toxicity profiles. By combining physicochemical property predictors and a critically evaluated database of biologically-acceptable substituents (with Hammett parameters), the medicinal chemist can reduce the number of derivative compounds that need to be synthesized to achieve optimal drug-like properties. The specifics of this software-assisted approach will be outlined using the drug acetyl sulfadiazine as well as other relevant examples.

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